Pancreatology 13 (2013) 594e597
Contents lists available at ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Original article
Electroacupuncture treatment for pancreatic cancer pain: A randomized controlled trial Hao Chen a, Tang-Yi Liu b, Le Kuai b, *, Ji Zhu a, Cai-Jun Wu a, Lu-Ming Liu a a b
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China College of Acupuncture and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 July 2013 Received in revised form 1 October 2013 Accepted 15 October 2013
Background: Pancreatic cancer is often accompanied by severe abdominal or back pain. It’s the first study to evaluate the analgesic effect of electroacupuncture on pancreatic cancer pain. A randomized controlled trial compared electroacupuncture with control acupuncture using the placebo needle. Methods: Sixty patients with pancreatic cancer pain were randomly assigned to the electroacupuncture group (n ¼ 30) and the placebo control group (n ¼ 30). Patients were treated on Jiaji (Ex-B2) points T8eT12 bilaterally for 30 min once a day for 3 days. Pain intensity was assessed with numerical rated scales (NRS) before the treatment (Baseline), after 3 treatments, and 2 days follow-up. Results: Baseline characteristics were similar in the two groups. After 3 treatment, pain intensity on NRS decreased compared with Baseline (1.67, 95% confidence interval [CI] 1.46 to 1.87) in the electroacupuncture group; there was little change (0.13, 95% CI 0.08 to 0.35) in control group; the difference between two groups was statistically significant (P < 0.001). Follow-up also found a significant reduction in pain intensity in the electroacupuncture group compared with the control group (P < 0.001). Conclusions: Electroacupuncture was an effective treatment for relieving pancreatic cancer pain. Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Pancreatic cancer Pain Electroacupuncture
1. Introduction Pancreatic cancer is a disease with a dismal prognosis. In the United States, approximately 45,000 patients are diagnosed with pancreatic cancer annually, and nearly an equal number will die from the disease in 2013 [1]. It is the fourth most common cause of cancer-related deaths across the globe [2]. The mortality rate is so high because pancreatic cancer usually only produces the symptoms such as obstructive jaundice, gastric outlet obstruction and pain when it has already advanced [3]. Pain can be a significant feature of advanced pancreatic cancer, with 90% of patients reporting significant abdominal or back pain [4]. Pain management is one of the key parts of comprehensive therapy in the patients with pancreatic cancer, and it also affects their quality of life [5]. Opioid pharmacotherapy is the mainstay of treatment [6], radiotherapy and celiac plexus neurolysis also can relieve the pancreatic
* Corresponding author. College of Acupuncture and Tuina, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai 200032, China. Tel.: þ86 021 51322172; fax: þ86 021 51322264. E-mail address: [email protected] (L. Kuai).
cancer pain [7]. However, these managements are not uniformly effective and undesirable side effects often limit their use [8]. For these reasons, it is desirable to develop complementary and alternative method with increased efficacy and safety for relieving pancreatic cancer pain [9]. In the past decades, acupuncture analgesia has been widely used to relieve the cancer pain, and also can decrease the dose and side effects of analgesics [10,11]. More and more studies were focused on the acupuncture for cancer pain recently [12e 15]. The first systematic review of acupuncture for cancer pain published in 2005 only included three randomized clinical trials (RCTs) [12]. Another review published in 2010 included 7 RCTs [13]. The latest review published in 2012 included a total of 15 RCTs [14]. All of them showed that acupuncture might be an effective analgesic adjunctive method of cancer pain, and acupuncture plus drug therapy demonstrated a significant pain relief in comparison with drug therapy alone [14,15]. Future rigorous RCTs will be necessary to assess the clinical efficacy of acupuncture in this area. Therefore, the aim of this study was to evaluate the analgesic effect of electroacupuncture on pancreatic cancer pain.
1424-3903/$ e see front matter Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pan.2013.10.007
H. Chen et al. / Pancreatology 13 (2013) 594e597
595
2. Methods
2.3. Measurements
2.1. Study design and subjects
Pain intensity was assessed with NRS [16,17]. Numbers from 0 to 10 are used to describe painless or maximum pain. The patients were given an explanation of NRS and were asked to circle the number of their pain degree before treatment (Baseline, D0), after 1e3 treatments (D1e3), and 1, 2 days after the completion of treatment (D4, 5). These patients were also asked to record their consumption of analgesics and adverse events.
We conducted an RCT with blinded evaluation and statistical analysis of the results at Fudan University Shanghai Cancer Center (FUSCC). It was approved by the ethics committee of FUSCC (IRB081166-6). Participants were identified by faculty in the Department of Integrative Oncology at FUSCC and referred for assessment of eligibility and to obtain written informed consent. All patients were treated at FUSCC. They were recruited between April 2009 and September 2012. Inclusion in the study: (i) aged 18e75 years; (ii) histologically confirmed advanced pancreatic cancer at ⅢeⅣ stage of pancreatic cancer in staging system of Union for International Cancer Control (UICC); (iii) pain intensity 3e6 on a numeric rating scale (NRS) graduated from 0 to 10 [16,17]; (iv) stable dose of analgesics at least 72 h before randomization; (v) estimated survival time more than 1 month; (vi) never been treated by acupuncture. Patients were excluded if they had any disease leading to experience of pain (such as arthritis rheumatoid and prolapse of lumbar intervertebral disc); had contraindications for the use of acupuncture (such as severe allergies, bleeding tendency, infectious dermatosis and ulcer or scar at acupoints); or had history of cerebrovascular accident or spinal cord injury. After collecting baseline measures, the patients were randomly assigned to the electroacupuncture group and the placebo control group by using random number table. The random allocation sequence was in blocks of four, stratified on NRS for pain intensity (3e4 vs 5e6). 2.2. Treatment Electroacupuncture treatments were given by a hospital credentialed acupuncturist with >15 years of experience. Patients were treated in a comfortable prone position. Jiaji (Ex-B2) points form T8 to T12 bilaterally were chosen based on traditional Chinese medicine (TCM) theory and neurophysiologic basis of Jiaji points [18]. Disposable stainless steel filiform needles (40 mm in length and 0.30 mm in diameter, Hwato brand, Suzhou Medical Appliance Factory, China) were inserted perpendicularly into the points to a depth of 25 mm. After De Qi sensation was achieved, the handles of needles on homolateral T8-T12 Jiaji were respectively connected to the Han’s acupoint nerve stimulator (HANS-200E, Jisheng Medical Technology Co., Ltd., Nanjing, China) at a frequency of 2/100 Hz and a current of 1 mA with a disperse-dense waveform. The needles remained for 30 min. The treatment was given once a day for 3 days. Two days follow-up was done. For placebo acupuncture, sham placebo acupuncture needles (DongBang AcuPrime Acupuncture Inc., South Korea) were used [19,20]. Its validity and credibility have been well demonstrated [19,20]. The needles with blunt tips were quickly put onto the same points used in the electroacupuncture group without inserting into the skin. The needles on homolateral T8 and T12 Jiaji were then connected to the electric stimulator, but with zero frequency and electric current. All patients were requested to maintain the same analgesic drug treatment after randomization. In general, Indometacin Controlledrelease Tablets (IndocontinÒ) 75 mg every 24 h was used before initiating opioid analgesics. If adequate pain relief is not achieved, the patients received Tramadol Hydrochloride Sustained Release Tablets (TramcontinÒ) 100 mg every 12 h. Morphine Sulfate Sustained release Tablets (MS COTINÒ) was used on an around-theclock schedule to treat uncontrolled pain, with the daily dosages of the most cases between 20 mg and 40 mg.
2.4. Statistical analysis Based on the result of previous research [15], it was estimated that 24 patients per group would be necessary to demonstrate a difference of 2.1 on the NRS between two groups with a 2-sided significance level of 0.05 and 90% power. We increased this number to a maximum of 30 per group to allow up to 20% dropout rate. Comparison of the demographic and clinical variables between the treatment and control groups was performed by using the Chisquare test and independent-samples T test. Comparison of the means before and after treatment for a single group was performed by using the paired-samples T test. Significance for all tests was set at P < 0.05. Data were analyzed with SPSS Statistics 19 for Windows (SPSS Inc., IBM Business Analytics Software, Armonk, NY, USA). 3. Results Among 92 eligible patients approached, 60 patients consented and were randomly assigned to the electroacupuncture group or the control group (65% acceptance rate, Fig. 1). The groups were balanced on demographic and medical characteristics (Table 1). Among 60 patients randomized, 59 finished the 3 days treatment and 2 days follow-up. One patient in the control group dropped because analgesic was modified due to breakthrough pain before the third treatment, and he has been included in the analysis. Pain intensity on NRS decreased compared with Baseline after the first treatment (1.87, 95% confidence interval [CI] 1.68 to 2.06), the second treatment (1.90, 95% CI 1.75 to 2.05) and the third treatment (1.67, 95% CI 1.46 to 1.87) in the electroacupuncture group; there was little change after the first (0.17, 95% CI 0.006 to0.34), second (0.13, 95% CI 0.03 to 0.30) and third treatment (0.13, 95% CI 0.08 to 0.35) in the control group; the difference between two groups was statistically significant at D1(F ¼ 0.29, P < 0.001), D2(F ¼ 0.80, P < 0.001) and D3(F ¼ 1.59, P < 0.001). Follow-up at D4 and D5 also found a significant reduction in pain intensity in the electroacupuncture group compared with the control group (P < 0.001). Fig. 2 shows these values for 5 days. During the trial, no infection at treated points and no other adverse events were reported by the patients nor recorded by the clinicians. 4. Discussion Pain is the most common symptom treated by acupuncture. This is the first RCT to demonstrate the effect of acupuncture on pancreatic cancer pain. The cancer types reported in the previous clinical trials of acupuncture for the cancer pain were mostly various [12,14]. The participants often received semi-standardized acupuncture treatment, e.g. the use of a predetermined set of points combined with a set of points used flexibly [12e14,21]. Abdominal pain and back pain due to pancreatic cancer is particularly impressive because of its frequency, severity and amenability to celiac plexus blockade [22]. A standardized acupuncture
596
H. Chen et al. / Pancreatology 13 (2013) 594e597
Fig. 1. Recruitment and flow of subjects through trial.
Table 1 Demographic and medical characteristics of study participants. Characteristics Gender n(%) Male Female Age Mean (SD) Stage of cancer (UICC) n(%) Ⅲ Ⅳ Primary Site n(%) Head of pancreas Body of pancreas Tail of pancreas Hepatic metastases n(%) Yes No Baseline pain intensity on NRS n(%) Mean (SD) 3e4 5e6 Maximum level of analgesic drug (WHO level 1 to 3) n(%) No drug 1 2 3
Electroacupuncture (n ¼ 30)
Control (n ¼ 30)
p-value 0.598
19 (63.3) 11 (36.7)
treatment with the same points was used for each patient in this trial for the purpose of facilitating the clinical generalization in the future. The placebo needle was used in the control group to exclude the placebo analgesic effect of acupuncture [23]. The average survival of advanced pancreatic cancer patients is only 3e6 months [24]. Up to 90 percent of patients suffer from
20 (66.7) 10 (33.3) 0.747
60.1 (8.5)
59.1 (9.1) 0.172
6 (20.0) 24 (80.0)
4 (13.3) 26 (86.7)
10 (33.3) 12 (40.0) 8 (26.7)
12 (40.0) 14 (46.7) 4 (13.3)
20 (66.7) 10 (33.3)
18 (60.0) 12 (40.0)
0.262
0.424
0.969 4.87 (0.94) 13 (43.3) 17 (56.7)
4.93 (0.95) 12 (40.0) 18 (40.0) 0.424
8 14 5 3
(26.7) (46.7) (16.7) (10.0)
7 9 11 3
(23.3) (30.0) (36.7) (10.0)
Fig. 2. Mean scores of pain intensity on numeric rating scale in two groups are shown over time. Day 0 is baseline raw mean. Independent-samples T test: D1 (P < 0.001), D2 (P < 0.001), D3 (P < 0.001), D4 (P < 0.001), D5 (P < 0.001).
H. Chen et al. / Pancreatology 13 (2013) 594e597
significant pain, and the analgesic effect of pancreatic cancer pain could affect the prognosis of patients [25]. Therefore, we designed this short-duration RCT for pancreatic cancer pain and then the eligible patients were easy to consent. Hu et al. [26] and Zhou et al. [27] reported that acupuncture has better therapeutic effect on mild and moderate pain than severe pain. In our pilot study, 9 patients were recruited. Three of them had severe pain (NRS 7), three had moderate pain (NRS 5e6), and three had moderate or mild pain (NRS 3e4). Two of the three patients with severe pain hadn’t finished 3 treatments because their pain aggravated and the analgesic type or dose was changed. They withdrew from the trial. The dropout rate was 22%. Thus, only the patients with mild or moderate pain were included in our study. Also in this trial there is only one patient dropped because analgesic was modified. The effect of acupuncture for severe pancreatic cancer pain should be specifically studied. Mechanism of causing pancreatic cancer pain is not very clear at present [28]. Some studies showed that neuropathic pain maybe the main reason for pancreatic cancer pain [22]. Pancreatic cancer pain is directly related to pancreatic cancer cells infiltrating in peripheral nerve [28]. Segmental dispersion of the sympathetic and parasympathetic systems is related to the location of Jiaji points [18], so Jiaji points were selected on the same nerve segments of the pancreas for treatment of pancreatic cancer pain and got the positive effect. After the treatment, pain intensity on NRS significantly decreased compared with Baseline in the electroacupuncture group; there was little change in the control group; the difference between two groups was statistically significant. Further exploration of analgesic mechanism of acupuncture for pancreatic cancer pain is greatly needed. Acupuncture is minimally invasive and has a very low incidence of adverse effects. No adverse effects related to the treatment were reported by patients nor recorded by the clinicians. One limitation of this study is that pain control was only assessed for 2 days after the procedure. All the participants were the untreated inpatients of Fudan University Shanghai Cancer Center. After the acupuncture trial, most of them were treated by chemotherapy based on the Gemcitabine (GemzarÒ), or the other treatments. Thus there is no evidence of sustained benefit. Furthermore, this was a single-center trial, and the study population was somewhat select. Therefore, generalizability of findings is limited. This study demonstrated that electroacupuncture can relieve the pain of pancreatic cancer patients. Group differences emerged as early as at D1 and remained significant at D5, 2 days after the completion of 3 treatments. On the basis of this trial, future multicenter, large-scale RCTs that have longer duration of treatment and follow-up, and the evaluation of blinding effectiveness of the active and the sham acupuncture, and include exploration of putative mechanisms are indicated. Acknowledgments This study was supported jointly by the National Natural Science Foundation of China (NSFC) (81202751 to Le Kuai), and Shanghai Science and Technology Committee (12401905600 to Hao Chen).
597
References [1] Siegel R, Naishadham D, Jemal A. Cancer statistics. 2013. CA Cancer J Clin 2013;63:11e30. [2] Hariharan D, Saied A, Kocher HM. Analysis of mortality rates for pancreatic cancer across the world. HPB (Oxf) 2008;10:58e62. [3] Koorstra JB, Hustinx SR, Offerhaus GJ, Maitra A. Pancreatic carcinogenesis. Pancreatology 2008;8:110e25. [4] Foley KM. Pain syndromes and pharmacologic management of pancreatic cancer pain. J Pain Symptom Manage 1988;3:176e87. [5] van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van KM, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007;18:1437e49. [6] Stjernsward J, Colleau SM, Ventafridda V. The World Health Organization cancer pain and palliative care program. Past, present, and future. J Pain Symptom Manage 1996;12:65e72. [7] de Leon-Casasola OA. Critical evaluation of chemical neurolysis of the sympathetic axis for cancer pain. Cancer Control 2000;7:142e8. [8] Negus SS, Vanderah TW, Brandt MR, Bilsky EJ, Becerra L, Borsook D. Preclinical assessment of candidate analgesic drugs: recent advances and future challenges. J Pharmacol Exp Ther 2006;319:507e14. [9] Bardia A, Barton DL, Prokop LJ, Bauer BA, Moynihan TJ. Efficacy of complementary and alternative medicine therapies in relieving cancer pain: a systematic review. J Clin Oncol 2006;24:5457e64. [10] Lu W, Dean-Clower E, Doherty-Gilman A, Rosenthal DS. The value of acupuncture in cancer care. Hematol Oncol Clin North Am 2008;22:631e48. [11] NIH consensus conference: acupuncture. JAMA 1998;280:1518e24. [12] Lee H, Schmidt K, Ernst E. Acupuncture for the relief of cancer-related pain-a systematic review. Eur J Pain 2005;9:437e44. [13] Peng H, Peng HD, Xu L, Lao LX. Efficacy of acupuncture in treatment of cancer pain: a systematic review. Zhong Xi Yi Jie He Xue Bao 2010;8:501e9. [14] Choi TY, Lee MS, Kim TH, Zaslawski C, Emst E. Acupuncture for the treatment of cancer pain: a systematic review of randomised clinical trials. Support Care Cancer 2012;20:1147e58. [15] Alimi D, Rubino C, Pichard-Leandri E, Zaslawski C, Ernst E. Analgesic effect of auricular acupuncture for cancer pain: a randomized, blinded, controlled trial. J Clin Oncol 2003;21:4120e6. [16] Caraceni A, Zecca E, Martini C, Pigni A, Gorni G, Galbiati A, et al. The validity of average 8-h pain intensity assessment in cancer patients. Eur J Pain 2010;14: 441e5. [17] Ferreira-Valente MA, Pais-Ribeiro JL, Jensen MP. Validity of four pain intensity rating scales. Pain 2011;152:2399e404. [18] Cabioglu MT, Arslan G. Neurophysiologic basis of back-Shu and Huatuo-Jiaji points. Am J Chin Med 2008;36:473e9. [19] Park J, White A, Stevinson C, Ernst E, James M. Validating a new nonpenetrating sham acupuncture device: two randomised controlled trials. Acupunct Med 2002;20:168e74. [20] Smith P, Mosscrop D, Davies S, Sloan P, Al-Ani Z. The efficacy of acupuncture in the treatment of temporomandibular joint myofascial pain: a randomised controlled trial. J Dent 2007;35:259e67. [21] Garcia MK, McQuade J, Haddad R, Patel S, Lee R, Yang P, et al. Systematic review of acupuncture in cancer care: a synthesis of the evidence. J Clin Oncol 2013;31:952e60. [22] Cherny NI, Portenoy RK. The management of cancer pain. CA Cancer J Clin 1994;44:263e303. [23] Moffet HH. Sham acupuncture may be as efficacious as true acupuncture: a systematic review of clinical trials. J Altern Complement Med 2009;15:213e6. [24] Oliveira-Cunha M, Hadfield KD, Siriwardena AK, Newman W. EGFR and KRAS mutational analysis and their correlation to survival in pancreatic and periampullary cancer. Pancreas 2012;41:428e34. [25] Lindsay TH, Jonas BM, Sevcik MA, Kubota K, Halvorson KG, Ghilardi JR, et al. Pancreatic cancer pain and its correlation with changes in tumor vasculature, macrophage infiltration, neuronal innervation, body weight and disease progression. Pain 2005;119:233e46. [26] Hu X, Ling CQ, Zhou QH. Clinical observation on wrist-ankle acupuncture for treatment of pain of middle-late liver cancer. Zhongguo Zhen Jiu 2004;24: 149e51. [27] Zhou Y, Zhong Y, Huang QF. Acupuncture plus three-step analgesic ladder principle for cancer pain relief: clinical observation on 24 cases. J Acupunct Tuina Sci 2007;5:162e5. [28] Koide N, Yamada T, Shibata R, Mori T, Fukuma M, Yamazaki K, et al. Establishment of perineural invasion models and analysis of gene expression revealed an invariant chain (CD74) as a possible molecule involved in perineural invasion in pancreatic cancer. Clin Cancer Res 2006;12:2419e26.
Contents lists available at ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Original article
Electroacupuncture treatment for pancreatic cancer pain: A randomized controlled trial Hao Chen a, Tang-Yi Liu b, Le Kuai b, *, Ji Zhu a, Cai-Jun Wu a, Lu-Ming Liu a a b
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China College of Acupuncture and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 July 2013 Received in revised form 1 October 2013 Accepted 15 October 2013
Background: Pancreatic cancer is often accompanied by severe abdominal or back pain. It’s the first study to evaluate the analgesic effect of electroacupuncture on pancreatic cancer pain. A randomized controlled trial compared electroacupuncture with control acupuncture using the placebo needle. Methods: Sixty patients with pancreatic cancer pain were randomly assigned to the electroacupuncture group (n ¼ 30) and the placebo control group (n ¼ 30). Patients were treated on Jiaji (Ex-B2) points T8eT12 bilaterally for 30 min once a day for 3 days. Pain intensity was assessed with numerical rated scales (NRS) before the treatment (Baseline), after 3 treatments, and 2 days follow-up. Results: Baseline characteristics were similar in the two groups. After 3 treatment, pain intensity on NRS decreased compared with Baseline (1.67, 95% confidence interval [CI] 1.46 to 1.87) in the electroacupuncture group; there was little change (0.13, 95% CI 0.08 to 0.35) in control group; the difference between two groups was statistically significant (P < 0.001). Follow-up also found a significant reduction in pain intensity in the electroacupuncture group compared with the control group (P < 0.001). Conclusions: Electroacupuncture was an effective treatment for relieving pancreatic cancer pain. Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Pancreatic cancer Pain Electroacupuncture
1. Introduction Pancreatic cancer is a disease with a dismal prognosis. In the United States, approximately 45,000 patients are diagnosed with pancreatic cancer annually, and nearly an equal number will die from the disease in 2013 [1]. It is the fourth most common cause of cancer-related deaths across the globe [2]. The mortality rate is so high because pancreatic cancer usually only produces the symptoms such as obstructive jaundice, gastric outlet obstruction and pain when it has already advanced [3]. Pain can be a significant feature of advanced pancreatic cancer, with 90% of patients reporting significant abdominal or back pain [4]. Pain management is one of the key parts of comprehensive therapy in the patients with pancreatic cancer, and it also affects their quality of life [5]. Opioid pharmacotherapy is the mainstay of treatment [6], radiotherapy and celiac plexus neurolysis also can relieve the pancreatic
* Corresponding author. College of Acupuncture and Tuina, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai 200032, China. Tel.: þ86 021 51322172; fax: þ86 021 51322264. E-mail address: [email protected] (L. Kuai).
cancer pain [7]. However, these managements are not uniformly effective and undesirable side effects often limit their use [8]. For these reasons, it is desirable to develop complementary and alternative method with increased efficacy and safety for relieving pancreatic cancer pain [9]. In the past decades, acupuncture analgesia has been widely used to relieve the cancer pain, and also can decrease the dose and side effects of analgesics [10,11]. More and more studies were focused on the acupuncture for cancer pain recently [12e 15]. The first systematic review of acupuncture for cancer pain published in 2005 only included three randomized clinical trials (RCTs) [12]. Another review published in 2010 included 7 RCTs [13]. The latest review published in 2012 included a total of 15 RCTs [14]. All of them showed that acupuncture might be an effective analgesic adjunctive method of cancer pain, and acupuncture plus drug therapy demonstrated a significant pain relief in comparison with drug therapy alone [14,15]. Future rigorous RCTs will be necessary to assess the clinical efficacy of acupuncture in this area. Therefore, the aim of this study was to evaluate the analgesic effect of electroacupuncture on pancreatic cancer pain.
1424-3903/$ e see front matter Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pan.2013.10.007
H. Chen et al. / Pancreatology 13 (2013) 594e597
595
2. Methods
2.3. Measurements
2.1. Study design and subjects
Pain intensity was assessed with NRS [16,17]. Numbers from 0 to 10 are used to describe painless or maximum pain. The patients were given an explanation of NRS and were asked to circle the number of their pain degree before treatment (Baseline, D0), after 1e3 treatments (D1e3), and 1, 2 days after the completion of treatment (D4, 5). These patients were also asked to record their consumption of analgesics and adverse events.
We conducted an RCT with blinded evaluation and statistical analysis of the results at Fudan University Shanghai Cancer Center (FUSCC). It was approved by the ethics committee of FUSCC (IRB081166-6). Participants were identified by faculty in the Department of Integrative Oncology at FUSCC and referred for assessment of eligibility and to obtain written informed consent. All patients were treated at FUSCC. They were recruited between April 2009 and September 2012. Inclusion in the study: (i) aged 18e75 years; (ii) histologically confirmed advanced pancreatic cancer at ⅢeⅣ stage of pancreatic cancer in staging system of Union for International Cancer Control (UICC); (iii) pain intensity 3e6 on a numeric rating scale (NRS) graduated from 0 to 10 [16,17]; (iv) stable dose of analgesics at least 72 h before randomization; (v) estimated survival time more than 1 month; (vi) never been treated by acupuncture. Patients were excluded if they had any disease leading to experience of pain (such as arthritis rheumatoid and prolapse of lumbar intervertebral disc); had contraindications for the use of acupuncture (such as severe allergies, bleeding tendency, infectious dermatosis and ulcer or scar at acupoints); or had history of cerebrovascular accident or spinal cord injury. After collecting baseline measures, the patients were randomly assigned to the electroacupuncture group and the placebo control group by using random number table. The random allocation sequence was in blocks of four, stratified on NRS for pain intensity (3e4 vs 5e6). 2.2. Treatment Electroacupuncture treatments were given by a hospital credentialed acupuncturist with >15 years of experience. Patients were treated in a comfortable prone position. Jiaji (Ex-B2) points form T8 to T12 bilaterally were chosen based on traditional Chinese medicine (TCM) theory and neurophysiologic basis of Jiaji points [18]. Disposable stainless steel filiform needles (40 mm in length and 0.30 mm in diameter, Hwato brand, Suzhou Medical Appliance Factory, China) were inserted perpendicularly into the points to a depth of 25 mm. After De Qi sensation was achieved, the handles of needles on homolateral T8-T12 Jiaji were respectively connected to the Han’s acupoint nerve stimulator (HANS-200E, Jisheng Medical Technology Co., Ltd., Nanjing, China) at a frequency of 2/100 Hz and a current of 1 mA with a disperse-dense waveform. The needles remained for 30 min. The treatment was given once a day for 3 days. Two days follow-up was done. For placebo acupuncture, sham placebo acupuncture needles (DongBang AcuPrime Acupuncture Inc., South Korea) were used [19,20]. Its validity and credibility have been well demonstrated [19,20]. The needles with blunt tips were quickly put onto the same points used in the electroacupuncture group without inserting into the skin. The needles on homolateral T8 and T12 Jiaji were then connected to the electric stimulator, but with zero frequency and electric current. All patients were requested to maintain the same analgesic drug treatment after randomization. In general, Indometacin Controlledrelease Tablets (IndocontinÒ) 75 mg every 24 h was used before initiating opioid analgesics. If adequate pain relief is not achieved, the patients received Tramadol Hydrochloride Sustained Release Tablets (TramcontinÒ) 100 mg every 12 h. Morphine Sulfate Sustained release Tablets (MS COTINÒ) was used on an around-theclock schedule to treat uncontrolled pain, with the daily dosages of the most cases between 20 mg and 40 mg.
2.4. Statistical analysis Based on the result of previous research [15], it was estimated that 24 patients per group would be necessary to demonstrate a difference of 2.1 on the NRS between two groups with a 2-sided significance level of 0.05 and 90% power. We increased this number to a maximum of 30 per group to allow up to 20% dropout rate. Comparison of the demographic and clinical variables between the treatment and control groups was performed by using the Chisquare test and independent-samples T test. Comparison of the means before and after treatment for a single group was performed by using the paired-samples T test. Significance for all tests was set at P < 0.05. Data were analyzed with SPSS Statistics 19 for Windows (SPSS Inc., IBM Business Analytics Software, Armonk, NY, USA). 3. Results Among 92 eligible patients approached, 60 patients consented and were randomly assigned to the electroacupuncture group or the control group (65% acceptance rate, Fig. 1). The groups were balanced on demographic and medical characteristics (Table 1). Among 60 patients randomized, 59 finished the 3 days treatment and 2 days follow-up. One patient in the control group dropped because analgesic was modified due to breakthrough pain before the third treatment, and he has been included in the analysis. Pain intensity on NRS decreased compared with Baseline after the first treatment (1.87, 95% confidence interval [CI] 1.68 to 2.06), the second treatment (1.90, 95% CI 1.75 to 2.05) and the third treatment (1.67, 95% CI 1.46 to 1.87) in the electroacupuncture group; there was little change after the first (0.17, 95% CI 0.006 to0.34), second (0.13, 95% CI 0.03 to 0.30) and third treatment (0.13, 95% CI 0.08 to 0.35) in the control group; the difference between two groups was statistically significant at D1(F ¼ 0.29, P < 0.001), D2(F ¼ 0.80, P < 0.001) and D3(F ¼ 1.59, P < 0.001). Follow-up at D4 and D5 also found a significant reduction in pain intensity in the electroacupuncture group compared with the control group (P < 0.001). Fig. 2 shows these values for 5 days. During the trial, no infection at treated points and no other adverse events were reported by the patients nor recorded by the clinicians. 4. Discussion Pain is the most common symptom treated by acupuncture. This is the first RCT to demonstrate the effect of acupuncture on pancreatic cancer pain. The cancer types reported in the previous clinical trials of acupuncture for the cancer pain were mostly various [12,14]. The participants often received semi-standardized acupuncture treatment, e.g. the use of a predetermined set of points combined with a set of points used flexibly [12e14,21]. Abdominal pain and back pain due to pancreatic cancer is particularly impressive because of its frequency, severity and amenability to celiac plexus blockade [22]. A standardized acupuncture
596
H. Chen et al. / Pancreatology 13 (2013) 594e597
Fig. 1. Recruitment and flow of subjects through trial.
Table 1 Demographic and medical characteristics of study participants. Characteristics Gender n(%) Male Female Age Mean (SD) Stage of cancer (UICC) n(%) Ⅲ Ⅳ Primary Site n(%) Head of pancreas Body of pancreas Tail of pancreas Hepatic metastases n(%) Yes No Baseline pain intensity on NRS n(%) Mean (SD) 3e4 5e6 Maximum level of analgesic drug (WHO level 1 to 3) n(%) No drug 1 2 3
Electroacupuncture (n ¼ 30)
Control (n ¼ 30)
p-value 0.598
19 (63.3) 11 (36.7)
treatment with the same points was used for each patient in this trial for the purpose of facilitating the clinical generalization in the future. The placebo needle was used in the control group to exclude the placebo analgesic effect of acupuncture [23]. The average survival of advanced pancreatic cancer patients is only 3e6 months [24]. Up to 90 percent of patients suffer from
20 (66.7) 10 (33.3) 0.747
60.1 (8.5)
59.1 (9.1) 0.172
6 (20.0) 24 (80.0)
4 (13.3) 26 (86.7)
10 (33.3) 12 (40.0) 8 (26.7)
12 (40.0) 14 (46.7) 4 (13.3)
20 (66.7) 10 (33.3)
18 (60.0) 12 (40.0)
0.262
0.424
0.969 4.87 (0.94) 13 (43.3) 17 (56.7)
4.93 (0.95) 12 (40.0) 18 (40.0) 0.424
8 14 5 3
(26.7) (46.7) (16.7) (10.0)
7 9 11 3
(23.3) (30.0) (36.7) (10.0)
Fig. 2. Mean scores of pain intensity on numeric rating scale in two groups are shown over time. Day 0 is baseline raw mean. Independent-samples T test: D1 (P < 0.001), D2 (P < 0.001), D3 (P < 0.001), D4 (P < 0.001), D5 (P < 0.001).
H. Chen et al. / Pancreatology 13 (2013) 594e597
significant pain, and the analgesic effect of pancreatic cancer pain could affect the prognosis of patients [25]. Therefore, we designed this short-duration RCT for pancreatic cancer pain and then the eligible patients were easy to consent. Hu et al. [26] and Zhou et al. [27] reported that acupuncture has better therapeutic effect on mild and moderate pain than severe pain. In our pilot study, 9 patients were recruited. Three of them had severe pain (NRS 7), three had moderate pain (NRS 5e6), and three had moderate or mild pain (NRS 3e4). Two of the three patients with severe pain hadn’t finished 3 treatments because their pain aggravated and the analgesic type or dose was changed. They withdrew from the trial. The dropout rate was 22%. Thus, only the patients with mild or moderate pain were included in our study. Also in this trial there is only one patient dropped because analgesic was modified. The effect of acupuncture for severe pancreatic cancer pain should be specifically studied. Mechanism of causing pancreatic cancer pain is not very clear at present [28]. Some studies showed that neuropathic pain maybe the main reason for pancreatic cancer pain [22]. Pancreatic cancer pain is directly related to pancreatic cancer cells infiltrating in peripheral nerve [28]. Segmental dispersion of the sympathetic and parasympathetic systems is related to the location of Jiaji points [18], so Jiaji points were selected on the same nerve segments of the pancreas for treatment of pancreatic cancer pain and got the positive effect. After the treatment, pain intensity on NRS significantly decreased compared with Baseline in the electroacupuncture group; there was little change in the control group; the difference between two groups was statistically significant. Further exploration of analgesic mechanism of acupuncture for pancreatic cancer pain is greatly needed. Acupuncture is minimally invasive and has a very low incidence of adverse effects. No adverse effects related to the treatment were reported by patients nor recorded by the clinicians. One limitation of this study is that pain control was only assessed for 2 days after the procedure. All the participants were the untreated inpatients of Fudan University Shanghai Cancer Center. After the acupuncture trial, most of them were treated by chemotherapy based on the Gemcitabine (GemzarÒ), or the other treatments. Thus there is no evidence of sustained benefit. Furthermore, this was a single-center trial, and the study population was somewhat select. Therefore, generalizability of findings is limited. This study demonstrated that electroacupuncture can relieve the pain of pancreatic cancer patients. Group differences emerged as early as at D1 and remained significant at D5, 2 days after the completion of 3 treatments. On the basis of this trial, future multicenter, large-scale RCTs that have longer duration of treatment and follow-up, and the evaluation of blinding effectiveness of the active and the sham acupuncture, and include exploration of putative mechanisms are indicated. Acknowledgments This study was supported jointly by the National Natural Science Foundation of China (NSFC) (81202751 to Le Kuai), and Shanghai Science and Technology Committee (12401905600 to Hao Chen).
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